Galanin coexists with tryptophane hydroxylase/5-HT in a majority of dorsal raphe nucleus (DRN) neurons, and the galanin receptors GalR1 and GalR2 are expressed at high concentrations in the DRN. By gene chipping analysis of 35,000 transcripts, we found that galanin is 1 of the 8 transcripts that are significantly elevated by at least 2 antidepressant treatments, fluoxetine and electroconvulsive therapy, in the rat DRN. Two (2) components of the galaninergic system, galanin and GalR2, were altered by these anti-depressant treatments: galanin mRNA levels were increased by 100% by both anti-depressant treatments, and fluoxetine (and desipramine) treatments induced a 50% increase in GalR2 binding sites in the rat DRN. Activation of GalR2 promotes calcium influx, neuronal firing, and neurogenesis, while activation GalR1 inhibits adenylyl cyclase and suppresses neuronal activity. Thus, a shift in the galaninergic transmission in the DRN towards a GalR2 mediated action following antidepressant treatments may enhance the activity of 5-HT neurons that express GalR2 and contribute to the elevation of synaptic 5-HT levels in terminal areas of these DRN neurons, such as frontal cortex and hippocampus. The functional significance of the elevated galaninergic activity in the DRN for the anti-depressant effects of fluoxetine is underlined by our data that a galanin receptor antagonist, M40, blocked the anti-depressant effects of fluoxetine, and 2 systemically active galanin receptor agonists, galnon, and galmic, produced an antidepressant like effect in the forced swim test. We aim at validating the GalR2 receptor as a target for new antidepressant drugs. We will focus on the galanin-5HT interactions in the DRN and their changes during anti-depressant drug treatment. Our experiments will be carried out in rats and transgenic mice strains that lack either GalR1 or GalR2. The planned work will deepen our knowledge of the galanin/5-HT system in the DRN and its contribution to the effects of anti-depressant treatments.